Skin is subject to abuse by many extrinsic (environmental) factors as well as intrinsic factors. A common extrinsic factor is exposure to ultraviolet radiation. Whether extrinsic or intrinsic, the abuse results in skin aging. Skin aging happens in two ways: (1) through the natural aging process which dermatologists call chronological aging (also known as chronoaging); and (2) through UV rays in sunlight accelerating the aging process which dermatologists call photoaging. Chronoaging results in thinning, loss of elasticity and general degradation of skin. As the skin naturally ages, there is a reduction in the cells and blood vessels that supply the skin. There is also a flattening of the dermal-epidermal junction which results in weaker mechanical resistance. As a consequence, older persons are more susceptive to blister formation in cases of mechanical traumas or disease processes (Oikarinen et al., Photodermatal. Photoimmunol. Photomed., 7:3-4 (1990)).
By contrast photoaging, or premature aging, is a process in which the skin changes in appearance as a result of repeated exposure to sunlight. Typically, photoaging occurs in areas of habitual exposure, such as the scalp, face, ears, neck, chest, forearms and hands. The changes associated with photoaging include elastosis, atrophy, wrinkling, vascular changes (diffuse erythema, ecchymoses, and telangiectasias), pigmentary changes (lentigines, freckles, and areas of hypo- and hyper-pigmentation), and the development of seborrheic keratosis, actinic keratosis, comedones and cysts.
Decreased elasticity of the cardiovascular system is one of the hallmarks of the normal aging process of mammals and has been linked to an age-related accumulation of advanced glycation endproducts (AGEs). Glycation is the product of reaction between a sugar and the free amino group of proteins and involves cross-linking. The linking of glycosylation byproducts to proteins results in the development of large, cross-linked molecules that inhibit the ability of the cell to function normally, thereby increasing the aging process. In addition, AGEs in tissues increase the rate of free radical production to 50-times the rate of free-radical production by unglycated proteins, even further increasing the rate of the aging process.
The relationship between sugar and the aging process is well established and is based upon the observation of diabetics, who seem to age rapidly. The irreversible cross-linked proteins of AGEs in vessel collagen also contribute to atherosclerosis, as well as to kidney failure-conditions worsened in diabetes (Diabetes 46(supp2):S19-S25 (1997)). It is also believed AGEs aggravate protein cross-linking in plaques and tangles of Alzheimer's Disease, thereby accelerating neuron death (Brain Research Review 23:134-143 (1997)). When glucose bonds with collagen, many negative effects can result, including thickened arteries, stiff joints, feeble muscles and failing organs. As collagen molecules in the cartilage and skin have a long lifetime (117 years for cartilage and 15 years for skin collagen), they are susceptible to the accumulation of AGEs since the protein turnover is a major determinant in AGE accumulation (Verzijl N., et al., J. Biol. Chem. 275(50):39027-31 (2000)). Reducing glycation within the body to slow the aging process has been recommended to improve lifestyle and foster a youthful appearance. This has been done with food, guiding patients in what they eat, and how they cook. (F. Wilson, Cosmetic Surgery Times, September, 2004).
Currently, scientists believe there are two major ways in which AGEs can form inside the body. One way is through a simple series of chemical reactions known as the “Maillard Pathway,” known from food chemistry for more than a century. During glycation, glucose binds to a protein bound nitrogen via a hydroxyl or carbonyl group. This intermediate then chemically rearranges to produce an Amadori product having two ketone groups on the second or third carbon of the glucose ring. This Amadori product goes through other rearrangements through the Maillard reaction. This is the basis for atherosclerosis, cataracts and other problems commonly associated with diabetes.
The second, discovered more recently, is based on a distinctly biological pathway, which only occurs within the cells because of the body's metabolism of carbohydrates or sugars. It is known that glucose and other saccharides are important glycating agents, but the most reactive glycating agents are the α-oxoaldehydes, glyoxal, methylglyoxal and 3-deoxyglucosone. Tissue-specific metabolic characteristics are understood to be involved in the degree of cellular protein modification by Maillard reactions, e.g., by modulation of the concentration of glycolysis intermediates or via specific defensive systems in these organs. (Portero-Otin, M., et al. Biochem. Soc. Trans. (2003) 31, 1403-1405.
AGEs are implicated as a major pathogenesis process in atherosclerosis, Alzheimer's Disease, the normal aging process, and the pathogenesis of the major microvascular complications of diabetes mellitus: nephropathy, neuropathy and retinopathy. In certain pathophysiological states, one or more of the following changes to glycation-related processes occurs: the rate of glycation is increased, the renal clearance of AGEs is decreased and/or the expression of AGEs receptors is increased leading to AGEs-related membrane thickening, AGEs-mediated cell activation, premature aging, and amyloidosis.
In the skin, glycation forms new AGEs in the extracellular matrix of the dermis and changes fibroblast shape and distribution, alters extracellular matrix molecules and the dermal-epidermal junction zone, increases β and α integrins concentration in the epidermal skin layer, and increases collagenase activity. (Pageon, H., et al., Ann N Y Acad Sci. 2005, 1043:529-32.)
The mechanism of action for AGEs inhibitors is understood to include both nucleophilic traps for reactive carbonyl AGE intermediates and antioxidant activity. AGE inhibitors are chelators of copper, and potent inhibitors of ascorbate oxidation. Because of the strong ascorbate oxidization inhibition properties of AGE inhibitors, these properties are believed to be the primary mechanism for the inhibition of AGE formation. (Price D L, et al., J Biol Chem. 2001 Dec. 28; 276(52):48967-72). AGEs are primarily eliminated from the circulation by scavenger receptor-mediated uptake in hepatic sinusoidal endothelial cells. (Hansen, B. et al., Diabetologia. 2002 October; 45(10):1379-88).
There are several drugs that inhibit the formation of AGEs; one such candidate is aminoguanidine. Aminoguanidine is structurally very similar to guanidine, the active ingredient in the herb, goat's rue (galega officinalis). It is believed that aminoguanidine acts by enhancing the action of nitric oxide (Brownlee, Diabetes, 2:57-60 (1992)). However, recently aminoguanidine has shown signs of toxicity in human trials (Okada et al., J. Nutr. Sci. Vitaminol., 41:43-50 (1995)).
In addition, it has been shown that thiamine pyrophosphate (TPP), the active coenzyme form of the B-complex vitamin thiamine, can stop late stage AGEs formation. TPP has also been shown to exert a two-pronged AGEs-inhibiting effect in the body. Boosting TPP in cells stressed by high glucose concentrations results in the opening of a “safety valve” in the normal metabolism of blood sugar through an enzyme known as transketolase. Activating transketolase allows the body to shunt excess triosephosphates, reactive glucose metabolic intermediates, transferring AGEs damage inside the cell into a safe alternative metabolic pathway, preventing their buildup and, concomitantly, preventing the formation of AGEs. Unfortunately, regular thiamine vitamin B is not readily absorbed and metabolized by the body. In addition, taking supplements comprising TPP is equally futile because specific enzymes strip TPP of its phosphate group, rendering the adulterated TPP ineffective to battle AGEs.
Another antiglycation compound, ALT-711, breaks the specific AGE-derived crosslinks between proteins, but does not disrupt the natural enzymatic glycosylation sites or peptide bonds of the collagen chain. ALT-711 has been shown to reduce age-related ventricular stiffness and improve cardiac function (Asif M, et al., Proceedings of the National Academy of Sciences USA, 97(6):2809-13; erratum:97(10):5679 (2000). ALT-711 also has been used to improve skin hydration of aged rats through oral and topical administration. (Vasan, S, et al., Arch Biochem. Biophys. 419(1):89-96 (2003).
Benfotiamine and B vitamins have previously been used in combination for the oral treatment of diabetic polyneuropathy (Stracke et al. Clin. Endocrinol. Diabetes 1996; 104(4):311-6) and alcoholic polyneuropathy (Woelk H, et al., Alcohol Alcohol. 1998 November-December; 33(6):631-8). However, neither of these references suggest topical applications for treating aging skin.
While AGEs-inhibiting drugs have displayed promise in regard to treating a number of conditions, including the reduction in the signs of aging, there is a clear need for the identification of new, safe AGE-inhibiting, non-prescription topical compositions that can be used to address the signs of skin aging caused by reactive carbonyl species (RCS), glycation of skin proteins, formation of advanced glycation endproducts (AGEs) and formation of advanced lipoxidation endproducts (ALEs).